The goal of this project is to identify the genes that predispose to human narcolepsy. Results from a study of the HLA complex in narcoleptic patients of several ethnic groups indicate that the susceptibility gene is located closer to the DQ than to the DR genes. Preliminary studies with additional polymorphic markers in the DQA1 and DQB1 promotor region and of a CA repeat located between the DQA1 and DQB1 genes also map to the narcolepsy susceptibility gene telomeric to DQB3 and centromeric to DQA1. One haplotype with DQB1-0602, but not DQA1-0102, was also identified in the control African American population but not in the narcoleptic population. These results suggest that both DQA1-0102 and DQB1- 0602 are needed for susceptibility to narcolepsy. To confirm these findings, the applicant will study more markers and more patients and analyze HLA haplotype segregation in multiplex families. The applicant also proposes to test the involvement of the canine narcolepsy (canarc-1) gene in human pathology.A linkage marker with high homology with the human mu-switch gene has been identified and cloned in narcoleptic Dobermans (current maximal LOD score = 10.8 at 0% recombination). Because of the likelihood of syntenic conservation of both the canine and human maps around canarc-1 and its human equivalent, the applicant will study the involvement of the canine gene in human patients by using both unrelated patients with narcolepsy and multiplex families. Together with the HLA association in humans, the discovery of a linkage of canarc-1 with an immunoglobulin heavy chain mu-switch-like gene suggests an immunopathology in both dogs and humans. The applicant therefore proposes to examine the possibility of linkage between narcolepsy and several immune- related loci that have been implicated in autoimmune diseases. These include the immunoglobulin gamma- and mu- switch genes on chromosome 14q32 and T cell receptor loci on chromosome 14q11 and 7q35.